The compound 2,6-bis(diethanolamino)-4,8-dipiperidinopyrimidopyrimidine, known as dipyridamole and referred to as such in the present specification, and some particular close analogues thereof have been known for some considerable time as effective vasodilator and thrombolytic agents, as disclosed for example in patent documents GB799177 and GB807826 which also describe various methods of synthesis of such compounds. Although the pharmacological activity of dipyridamole is diverse, in at least most cases it is believed to arise as a result of its ability to inhibit or modulate the transport of nucleosides across cell membranes, this nucleoside transport being a major factor which is often implicated in the development of antitumor drug resistance. Not only can dipyridamole directly modulate the activity of cytotoxic compounds which are themselves nucleosides, e.g. cytarabine, fluordeoxyuridine and deoxycoformycin, or which are bases that become converted within the cell into nucleosides, e.g. fluorouracil, but dipyridamole can also indirectly modulate the activity of antimetabolites whose cytotoxicity is influenced by levels of normal nucleosides (e.g. methotrexate, the thymidylate synthase inhibitor CB3717, acivicin and PALA). In addition it is also known that dipyridamole can act to increase in vitro cytotoxicity of drugs such as doxrubicin, vinblastine and etoposide. The mechanism of action in the case of the latter cytotoxic compounds appears to involve the induction of higher intracellular drug levels, and it is believed that this may be caused, in part, by dipyridamole inhibiting drug efflux.
These properties of dipyridamole have led to proposals for using it in therapy, especially antitumor therapy, in combination with a range of cytotoxic drugs so as to enhance or potentiate the cytotoxicity of the latter. However, although a high level of activity in enhancing or potentiating the cytotoxicity of such drugs has been demonstrated in some cases in the course of in vitro experiments, clinical testing and use of dipyridamole in this manner, i.e. in combination with cytotoxic drugs, has been severely handicapped by a problem of low solubility and difficulty in satisfactory formulation for effective administration, together with a major problem arising from the fact that dipyridamole has a strong binding affinity to a plasma protein, .alpha.-1 acid glycoprotein (AGP). This AGP protein is often present at elevated levels in cancer patients, and the effect of the strong AGP binding affinity of dipyridamole is to reduce the plasma or serum concentration of free dipyridamole. This in turn then reduces the ability of the dipyridamole to potentiate the activity of the drugs concerned since it seems that only free dipyridamole is able to modulate or inhibit the membrane transport of nucleosides and cytotoxic drugs.